Dose-related Outcomes Research Articles

Unblinding and demand characteristics in the treatment of depression

Blinding of treatment allocation in clinical trials in psychiatry is regarded as an ideal. The potential impact of unblinding chimes with a general concern for psychological research: so-called demand characteristics can undermine confidence in findings from experimental and clinical studies. Scepticism can result in nihilism. The reliance on subjective report of symptoms in clinical trials of drug efficacy in depression provides an important example. It is regularly implied that if subjective effects, including specific adverse reactions, unblind participants to an active treatment then evidence for its efficacy is suspect. In fact, the strong association between dose and subjective effects does not translate into a strong relationship with efficacy in randomised controlled trials (RCTs) of conventional antidepressant drugs; this observation falsifies the proposition that unblinding is the principal mechanism driving RCT outcomes in studies of depression. Instead, changes in brain function, that occur soon after treatment starts, do predict treatment outcomes and align with our understanding of neurotransmitter effects from neuroscience. Psychedelic experience for the treatment of depression must be unblinding, but the effect results directly from serotonergic receptor activation and changes in brain connectivity. Where such effects are part of a novel mechanism of action, a strong dose response relationship would be expected, irrespective of unblinding. We highlight the importance of exploring blinding as a mechanism, confirming dose-related outcomes, and dissociating unblinding effects from efficacy. Unblinding does not necessarily invalidate the subjective experience of sustained recovery from depression.

Context Matters: Exploring Intervention Dose and Dose-Related Outcomes in a Palliative Care Intervention for Patients with Heart Failure (SCI910)

Context Matters: Exploring Intervention Dose and Dose-Related Outcomes in a Palliative Care Intervention for Patients with Heart Failure (SCI910)

10-Year Paclitaxel Dose-Related Outcomes of Drug-Eluting Stents Treated Below the Knee in Patients with Chronic Limb-Threatening Ischemia (The PADI Trial)

PurposeRecently, two meta-analyses concluded that there appears to be an increased risk of long-term mortality of paclitaxel-coated balloons and stents in the superficial femoral and popliteal artery, and paclitaxel-coated balloons below the knee. In this post hoc study of the PADI Trial, we investigated the long-term safety of first-generation paclitaxel-coated drug-eluting stents (DES) below the knee and the dose–mortality relationships of paclitaxel in patients with chronic limb-threatening ischemia (CLI).Materials and MethodsThe PADI Trial compared paclitaxel-coated DES with percutaneous transluminal angioplasty with bail-out bare-metal stents (PTA ± BMS) in patients with CLI treated below the knee. Follow-up was extended to 10 years after the first inclusion, and survival analyses were performed. In addition, dose-related mortality and dose per patient weight-related mortality relations were examined.ResultsA total of 140 limbs in 137 patients were included in the PADI Trial. Ten years after the first inclusion, 109/137 (79.6%) patients had died. There was no significant difference between mortality in the DES group compared with the PTA ± BMS group (Log-rank p value = 0.12). No specific dose-related mortality (HR 1.00, 95% CI 0.99–1.00, p = 0.99) or dose per weight mortality (HR 1.05, 95% CI 0.93–1.18, p = 0.46) relationships were identified in the Cox-proportional Hazard models or by Kaplan–Meier survival analyses.ConclusionsThere is a poor 10-year survival in both paclitaxel-coated DES and PTA ± BMS in patients with CLI treated below the knee. No dose-related adverse effects of paclitaxel-coated DES were observed in our study of patients with CLI treated below the knee.Level of EvidenceThe PADI Trial: level 1, randomized clinical trial

Reducing the Burden of Diabetes Treatment: A Review of Low-cost Oral Hypoglycemic Medications.

The vast majority of individuals diagnosed with diabetes are low/middle income and may have access to only three of the 11 oral hypoglycemic medications (OHMs) due to cost: metformin intermediate release (IR) or extended release (ER), sulfonylureas (glimepiride, glipizide, glyburide), and pioglitazone. Sulfonylureas and pioglitazone have had significant controversy related to potential adverse events, but it remains unclear whether these negative outcomes are class, drug, or dose-related. We conducted a narrative review of low-cost OHMs. We evaluated the maximum recommended (MAX) compared to the most effective (EFF) daily dose, time-to-peak change in HbA1c levels, and adverse events of low-cost oral hypoglycemic medications. We found that the MAX was often greater than the EFF: metformin IR/ER (MAX: 2,550/2,000 mg, EFF: 1,500-2,000/1,500-2,000 mg), glipizide IR/ER (MAX: 40/20 mg, EFF: 20/5 mg), glyburide (MAX: 20 mg, EFF: 2.5-5.0 mg), pioglitazone (MAX: 45 mg, EFF: 45 mg). Time-to-peak change in HbA1c levels occurred at weeks 12-20 (sulfonylureas), 25-39 (metformin), and 25 (pioglitazone). Glimepiride was not associated with weight gain, hypoglycemia, or negative cardiovascular events relative to other sulfonylureas. Cardiovascular event rates did not increase with lower glyburide doses (p<0.05). Glimepiride and pioglitazone have been successfully used in renal impairment. Metformin, glimepiride, and pioglitazone are safe and efficacious OHMs. Prescribing at the EFF rather than the MAX may avoid negative dose-related outcomes. OHMs should be evaluated as individual drugs, not generalized as a class, due to different dosing and adverse-event profiles; Glimepiride is the preferred sulfonylurea since it is not associated with the adverse events as others in its class.

S11-03 - Evidence-based psychotherapy for chronic depression

BackgroundThe various forms of chronic depression account for about 1/3 of depressive disorders. Chronic depression is characterized by low rates of spontaneous remissions, requiring longer and more intense treatment than episodic depression. While considerable research has confirmed the efficacy of specific psychotherapies in the treatment of episodic depression, only few studies have addressed chronic depression.AimTo assess the efficacy of specific psychotherapies in chronic depression and to provide recommendations for future research.MethodSystematic review of the literature.ResultsIdentified studies varied largely regarding sample sizes, outcome criteria, and characteristics of treatment. Limited research suggests that more traditional approaches (CBT, IPT) have shown only modest success in the treatment of chronic depression. The Cognitive Behavioral Analysis System of Psychotherapy (CBASP), combining behavioural, cognitive, and interpersonal strategies, has demonstrated good efficacy in combination with medication in one large study so far. In general, combinations of pharmacotherapy and psychotherapy appear to improve treatment effects with regard to broader outcome criteria and longterm outcome.ConclusionA broader empirical basis is needed to allow firmer conclusions on the efficacy of different types of psychotherapy in chronic depression. Larger randomized studies are needed, particularly those investigating additive effects of combined treatment, comparisons of specific interventions, and dose-related outcomes. It may also be necessary to expand traditional short-term approaches by designing studies which explicitly adopt suggested model-specific options for chronicity. Studies should also consider possible predictors of outcome, such as early versus late onset and comorbidity, as well as health economic aspects.

Effect of Antiviral Treatment with Entecavir on Age- and Dose-Related Outcomes of Duck Hepatitis B Virus Infection

Entecavir (ETV), a potent inhibitor of the hepadnaviral polymerases, prevented the development of persistent infection when administered in the early stages of duck hepatitis B virus (DHBV) infection. In a preliminary experiment, ETV treatment commenced 24 h before infection showed no significant advantage over simultaneous ETV treatment and infection. In two further experiments 14-day-old ducks were inoculated with DHBV-positive serum containing 10(4), 10(6), 10(8), or 5 x 10(8) viral genomes (vge) and were treated orally with 1.0 mg/kg of body weight/day of ETV for 14 or 49 days. A relationship between virus dose and infection outcome was seen: non-ETV-treated ducks inoculated with 10(4) vge had transient infection, while ducks inoculated with higher doses developed persistent infection. ETV treatment for 49 days did not prevent initial infection of the liver but restricted the spread of infection more than approximately 1,000-fold, a difference which persisted throughout treatment and for up to 49 days after withdrawal. Ultimately, three of seven ETV-treated ducks resolved their DHBV infection, while the remaining ducks developed viremia and persistent infection after a lag period of at least 63 days. ETV treatment for 14 days also restricted the spread of infection, leading to marked and sustained reductions in the number of DHBV-positive hepatocytes in 7 out of 10 ducks. In conclusion, short-term suppression with ETV provides opportunity for the immune response to successfully control DHBV infection. Since DHBV infection of ducks provides a good model system for HBV infection in humans, it seems likely that ETV may be useful in postexposure therapy for HBV infection aimed at preventing the development of persistent infection.

Use of angiotensin-converting enzyme inhibitor therapy and dose-related outcomes in older adults with new heart failure in the community.

To evaluate the dose-related benefit of angiotensin-converting enzyme (ACE) inhibitor therapy among older adults with heart failure and to evaluate whether low-dose ACE inhibitor therapy is better than none. Observational cohort study. Community-dwelling older adults in Ontario, Canada. We identified 16539 adults 66 years or older who survived 45 days following their first heart failure hospitalization discharge. Multivariate techniques including propensity scores were used to study the association between the dose of ACE inhibitor therapy dispensed and 3 outcomes: survival, survival or heart failure rehospitalization, and survival or all-cause hospitalization at 1 year of follow-up. Logistic regression models explored the association between initial dose dispensed and subsequent dose reduction or drug cessation. Overall, 10793 (65.3%) of patients were dispensed ACE inhibitor therapy, with more than a third (3935; 36.5%) initiated on low-dose therapy. Relative to dispensing of low-dose ACE inhibitor therapy, nonuse was associated with increased mortality (hazard ratio [HR], 1.12; 95% confidence interval [CI], 1.02 to 1.22). Dispensing medium-dose therapy provided a benefit similar to low-dose (HR, 0.94; CI, 0.86 to 1.03) and dispensing of high-dose therapy was associated with improved survival benefit (HR, 0.76; CI, 0.68 to 0.85). Relative to dispensing of low-dose ACE inhibitor therapy, dispensing high-dose conferred a benefit (HR, 0.87; CI, 0.80 to 0.95) on the composite outcome of 1-year mortality or heart failure hospitalization and the composite outcome of 1-year mortality or all-cause hospitalization (HR, 0.87; CI, 0.81 to 0.93). Relative to those dispensed low-dose ACE inhibitor therapy, those initially dispensed high-dose therapy were twice as likely to have their subsequent dose reduced or the therapy discontinued (odds ratio, 2.36; CI, 2.07 to 2.69). Our findings suggest that when possible, older adults should be titrated to the higher doses of ACE inhibitor therapy evaluated in clinical trials. If older adults cannot tolerate higher doses, then low-dose ACE inhibitor therapy is superior to none. High-dose ACE inhibitor therapy is not as well tolerated as lower doses.

Characterization of Age- and Dose-Related Outcomes of Duck Hepatitis B Virus Infection

Experimental inoculation of naive ducks with duck hepatitis B virus (DHBV) can lead to one of three outcomes, namely, persistent viremia, transient infection with or without viremia, or no evidence of infection. The ability of individual ducks to resolve DHBV infection was found to be linked to the age of the duck at the time of inoculation and the dose of inoculated virus. (1) In recently hatched ducks inoculated intravenously (i.v.) with 4 × 104DHBV DNA genomes, a switch from persistent viremia to transient antibody appearance was seen at an age of inoculation between 7 and 14 days. A 25-fold increase in the dose of virus (1 × 106DHBV genomes) delayed this switch by 7 days. (2) When 4-month-old ducks were inoculated i.v. with different doses of virus, only those receiving the highest dose (2 × 1011DHBV genomes) showed viremia and extensive viral replication and histological changes in the liver; 2/3 ducks in this group had a transient infection, while the third duck had viral replication and histological changes in the liver that were still present at day 120 postinoculation (p.i.). In all ducks receiving lower doses (1 × 103, 1 × 106, 1 × 109DHBV genomes) antibodies to viral surface and core antigens developed without detectable viral replication in the liver on days 6, 9, or 12 p.i. (3) When 10- to 16-month-old ducks were inoculated i.v. with 2 × 1011DHBV genomes, all showed extensive viral replication in hepatocytes and mild to moderate histological changes in the liver on days 4 or 6 p.i. In 4/5 ducks viremia was not detected, anti-surface antibodies were first detected on day 8 p.i., and viral DNA and antigen were cleared from the liver by days 35–47 p.i. The remaining duck became viremic with persistence of virus in the liver until at least day 46 p.i. The findings of the study are consistent with a model for noncytopathic viruses (R. M. Zinkernagel (1996)Science271, 173–178).